Identification of a Serotonin 2A Receptor Subtype of Schizophrenia Spectrum Disorders With Pimavanserin: The Sub-Sero Proof-of-principle Study
试验速览
- 阶段
- 2 期
- 状态
- 撤回
- 发起方
- 主要终点
- Reduction in positive symptoms - Clinical response in patients after 6 weeks of treatment
研究概览
简要总结
Schizophrenia is a severe, often chronic mental disorder, characterized by positive and negative symptoms and cognitive deficits. The serotonin hypothesis of schizophrenia was proposed in the 1950s, but only recently, pimavanserin, the first antipsychotic medication with selective affinity for the serotonin 2A receptor was approved.
The aim of this translational proposal is to test the clinical validity of the serotonin hypothesis of schizophrenia and to guide development of operational, objective criteria for stratification of first-episode schizophrenia spectrum patients before antipsychotic treatment.
Our previous data have strongly suggested, that a subgroup of antipsychotic-naïve patients will respond to serotonin 2A receptor (2AR) blockade. This treatment will cause minimal side-effects compared with conventional dopamine D2/3 receptor blockade.
In this Danish, investigator-initiated trial, we will establish a cohort of 40 antipsychotic-free, first-episode schizophrenia spectrum patients and enrol them in a 6-week open label, one-armed trial with selective serotonin 2AR blockade (pimavanserin).
Before initiation of pimavanserin patients will undergo: positron emission tomography (PET) imaging of the serotonin 2AR binding potential using the radioligand [¹¹C]Cimbi-36; magnetic resonance spectroscopy (MRS) of cerebral glutamate levels; structural Magnetic Resonance imaging (MRI), including Diffusion Tensor Imaging (DTI); cognitive and psychopathological examinations; Electrocardiography (ECG), and blood sampling for genetic- and metabolic analyses.
Matched healthy controls will undergo parallel examinations, but not medical treatment and PET .
ACADIA Pharmaceuticals Inc. provides the study medication (pimavanserin). ACADIA had no influence on study design and will not take part in data processing or publication of the results of the study.
详细描述
(More information will follow on study approval).
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 45 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Antipsychotic-free (as defined under Exclusion Criteria below)
- •Fulfilling the diagnostic criteria of schizophrenia, persistent delusional disorder, acute and transient psychotic disorders, schizoaffective disorder, other non-organic psychotic disorders and unspecified non-organic disorders (ICD-10: F20.x; F22.x; F23.x; F24.x; F25.x; F28; F29); verified by The Schedules for Clinical Assessment in Neuropsychiatry (SCAN) 2.0 interview (Wing et al. 1990)
- •Age: 18-45 years
- •Legally competent (In Danish: 'myndige og habile i retslig forstand')
排除标准
- •Prior use of antipsychotic medication longer than an episode of two weeks in the previous year and/or 6 weeks lifetime, and/or antipsychotic treatment within 30 days prior to inclusion.
- •Current substance abuse ICD-10 (F1x.2) or substance abuse in any period up to 3 months prior to referral (exception: tobacco/nicotine, F17.2)
- •Head injury with more than 5 minutes of unconsciousness
- •Any coercive measure
- •Metal implanted by operation
- •Pacemaker
- •Pregnancy (assessed by urine human chorionic gonadotropin (HCG))
- •Female patients: Unwillingness to use safe contraception (Intra Uterine Device/System or hormonal contraceptives) during the study period including the wash out period.
- •Severe physical illness
- •Known QT prolongation or congenital prolongation of the QT interval
- •Medical history of cardiac arrhythmias, as well as other circumstances that may increase the risk of the occurrence of torsade de pointes and/or sudden death, including symptomatic bradycardia, hypokalemia or hypomagnesemia
- •Current treatment with drugs known to prolong QT interval including: Class 1A antiarrhythmics (e.g., quinidine, procainamide); Class 3 antiarrhythmics (e.g., amiodarone, sotalol); certain antibiotics (e.g., gatifloxacin, moxifloxacin).
- •Allergies to any of the inactive ingredients and film coat components: pregelatinized starch, magnesium stearate, microcrystalline cellulose, hypromellose, talc, titanium dioxide, polyethylene glycol, and saccharin sodium.
- •Healthy controls - Inclusion Criteria:
- •Matched with patients on age (+/- 2 years), sex and parental socioeconomic status
- •Age 18-45 years
- •Legally competent (In Danish: 'myndige og habile i retslig forstand')
- •Recruitment: through online advertisement (www.forsøgsperson.dk)
- •Healthy controls - Exclusion Criteria:
- •Any psychiatric illness any first-degree relatives with known psychiatric diagnoses or physical disease
- •Substance abuse during the past 3 months or positive urine-screening of illegal drugs
- •Head injury with more than 5 minutes of unconsciousness
- •Components of metal implanted by operation
- •Pacemaker
- •Pregnancy (assessed by urine HCG)
- •Severe physical illness
研究组 & 干预措施
Patients
40 antipsychotic-free, first-episode schizophrenia spectrum patients will receive 6 weeks of treatment with a selective serotonin 2A Receptor (2AR) blockade.
Before initiation of treatment patients will undergo: positron emission tomography (PET) imaging of the serotonin 2AR binding potential using the radioligand [¹¹C]Cimbi-36; magnetic resonance spectroscopy (MRS) of cerebral glutamate levels; structural Magnetic Resonance Imaging (MRI), including diffusion tensor imaging (DTI); cognitive and psychopathological examinations; Electrocardiography (ECG), and blood sampling for genetic- and metabolic analyses.
(Full description will be updated on approval).
干预措施: Pimavanserin 34 milligrams (MG) [Nuplazid] (Drug)
结局指标
主要结局
Reduction in positive symptoms - Clinical response in patients after 6 weeks of treatment
时间窗: 6 weeks
Reduction in the Positive and Negative Syndrome Scale (PANSS) positive subscale score \[PANSS positive baseline - PANSS positive week 6\]. To assess a patient using PANSS, an approximately 45-minute clinical interview is conducted. The patient is rated from 1 to 7 on 30 different symptoms based on the interview as well as reports of family members or primary care hospital workers.\[4\] Positive scale 7 Items, (minimum score = 7, maximum score = 49) Negative scale 7 Items, (minimum score = 7, maximum score = 49) General Psychopathology scale 16 Items, (minimum score = 16, maximum score = 112) For the primary outcome only the chance in PANSS positive scores will be reported.
次要结局
- Reduction in positive symptoms after week 2 and 4 - Secondary clinical endpoints(6 weeks)
- Response in cognitive functioning using CANTAB after 6 weeks of treatment.(6 weeks)
- Reduction in negative symptoms after 6 weeks of treatment, measured with the Brief Negative Symptom Scale (BNSS).(6 weeks)
- Reduction in obsessive symptoms after 6 weeks of treatment, measured with The Brief Obsessive Compulsive Scale (BOCS).(6 weeks)
- The proportion of patients achieving symptomatic remission (using the Andreasen criteria) at week 6.(6 weeks)
- The serotonin 2AR binding potential in relation to treatment response(6 weeks)
- Characterization of para-clinical parameters in patients using both genetic high-density-snip-arrays and clinical blood markers.(6 weeks)
- Characterization of response in Magnetic Resonance Imaging parameters after 6 weeks of treatment.(6 weeks)
研究者
Bjorn H. Ebdrup
MD PhD, associate professor, vice-chair of research CNSR
University of Copenhagen